1. Field of the Invention
This invention relates to an oral drug delivery system having delayed gastrointestinal transit. More specifically it relates to a gastric retention system for controlled release of drugs to the gastrointestinal tract. The system comprises one or more non-continuous compressible elements, i.e., retention arms, and an attached controlled release device and which in the expanded form resists gastrointestinal transit. It further relates to a modular system for use therein comprising one or more non-continuous compressible elements and an attached receptacle means for receiving and holding a drug-containing orally administrable controlled release device and which in the expanded form resists gastrointestinal transit.
2. Description of the Prior Art
Means for achieving retention of drugs in the gastrointestinal tract and for controlled release of said drugs therein ahs been a long sought objective. Upon per os administration of a drug or drug preparation most, if not all of it, usually passes from the stomach to the small intestine in a relatively short time, generally on the order of one to two hours. This behavior necessitates frequent per os administration of a drug, the beneficial effect of which is to be exhibited in the stomach or the wall thereof. For some drugs, efficient absorption occurs only in the upper gastrointestinal tract, i.e., the stomach and/or the small intestine. Slow release formulations of such drugs may only be effective for a short time period, generally 4-5 hours, because the formulation passes into the colon, where drug absorption may be inefficient or nonexistent. In such cases, retention of a controlled release drug preparation in the upper gastrointestinal tract would be advantageous.
Retention of drugs or drug formulations in the proximal region of the gastrointestinal tract in order for said drug or formulation to achieve its beneficial effect poses a difficult problem. Davis et al., Int. J. Pharm. 21, 331-340 (1984) teach that gastrointestinal transit of a pharmaceutical dosage form depends upon several factors such as size, shape and nature of the system; i.e., whether single unit or multiparticulate; and upon physiological factors, especially upon the presence or absence of food in the stomach. The stomach is known to empty different materials at different rates and to break down digestible materials to about 2 mm or less before they pass through the pylorus into the duodenum. Meals of high calorific value and certain foodstuffs, especially fats, appear to have an inhibitor effect on gastric emptying [Davis et al., Int. J. Pharm. 21, 167-177, (1984)].
Retention of indigestible materials in an empty stomach is further complicated by the ability of the gastrointestinal tract to undergo powerful contractions called the interdigestive myoelectric complex (IMC), also known as interdigestive migrating motor complex, or more simply, "housekeeper wave". This phenomenon tends to sweep indigestible materials from an empty stomach past the pylorus into the duodenum and through the remainder of the small intestine.
Various methods have been described in the literature in efforts to achieve retention and controlled release of drugs in the gastrointestinal tract.
U.S. Pat. No. 3,976,764, issued Aug. 24, 1976, describes hollow globular shells having an undercoating of a cellulose acetate-phthalate copolymer and an outer coating of ethyl and hydroxypropyl celluloses in combination with a pharmaceutically active ingredient. Said coated globular shells are reported to float in the gastric juices when taken internally to provide prolonged release of the active ingredient. Other flotation devices are described in U.S. Pat. Nos. 4,140,755 and 4,167,558.
EP Application 0168862, published Jan. 22, 1986, describes biodegradable hollow fibers containing an active substance in their cavities for controlled release of said substance when implanted subcutaneously in mammals. U.S. patent application Ser. No. 38,189, filed Apr. 14, 1987 describes drug-containing fibers having an axial ratio of at least about 8 which are useful for retention in the gastrointestinal tract.
Mitra, Polymer Preprints, ACS Div. Polymer Chemistry, 24 (1), 51-52 (1983), and U.S. Pat. No. 4,451,260, issued May 29, 1984, describes an oral sustained release drug delivery system, a laminate, comprising a carrier film containing drug in a matrix and a barrier film on one or both surfaces of the carrier film. The barrier film serves to control the rate of release of the drug and also provides buoyancy to the delivery system by virtue of air bubbles between it and the carrier film. The composite is generally cut into long narrow strips 2.1.times.14 cm.sup.2, optionally pleated before being packed into gelatin capsules.
EP 202159, published Nov. 20, 1986, describes gastric retention devices comprising a continuous solid-stick figure, a planar figure or ring figure made from polymers. A drug may be dispersed within the device as an integral part thereof, or may be attached as a controlled release drug module to the aforementioned retention devices.
Orally administrable devices of variable geometry; i.e., devices which have one configuration designed to permit their oral administration and which, when in the environment of use, assume a second configuration designed to prevent their expulsion are known in the literature. Principle focus upon such devices has occurred in animal husbandry and particularly in the treatment of ruminants. Representative of such devices are those disclosed in U.S. Pat. No. 3,844,285 and 4,601,893.
In spite of the developments in gastric retention devices the need for practical means for achieving retention of drugs or drug formulations in the stomach for controlled (sustained, predictable and reproducible) release of drugs regardless of whether the stomach is full, empty or anywhere in between is highly desirable. Especially desirable is such a system which can be applied to existing orally administrable controlled release devices to enhance their gastric retention so as to render them essentially independent of the condition of the stomach.